Emesis is a common and serious problem in patients receiving cancer chemotherapeutic agents. In a significant number of patients, nausea and vomiting is so severe that they discontinue their course of chemotherapeutic treatment prior to its completion. Although no known antiemetic agent is totally effective in alleviating the emesis associated with chemotherapy, there are a large number of compounds (many based on the substituted benzamide structure) which have good antiemetic activity.
Although the complete mechanism of action of antiemetic agents is not known, the effective antiemetic agents are generally dopaminergic antagonists. Indeed, screening for potential antiemetic agents typically is conducted via tests designed to determine dopaminergic blockage, e.g. spiperone binding tests in vitro and apomorphine emesis tests in dogs. As a result of their dopaminergic antagonism and/or central nervous system depression, known antiemetic agents have undesirable side effects such as sedation, dystonic reactions, diarrhea and akathisia.
We have surprisingly found a group of substituted benzamide antiemetic agents with a high specificity of action, which are not dopaminergic antagonists and which are free of the undesirable side effects of the presently known antiemetic agents.
An excellent, modern review article on the variously substituted benzamides and their pharmacological activities is found in "Chemical Regulation of Biological Mechanisms", A. M. Creighton and S. Turner, editors, Royal Society of London (1982), in the chapter entitled "Substituted Benzamides as Dopamine Antagonists", by M. S. Hadley (Pages 140-153). It states that this class of compounds is defined by the formulae ##STR3## in which the aryl ring is most commonly the phenyl ring and where "a methoxy group ortho to the benzamide moiety is almost invariably present." It points out that the diverse actions of the substituted benzamides can be considered as being a consequence of the compounds being dopamine antagonists.
Representative prior art patents disclosing N-substituted benzamides, having various substituents on the phenyl ring, include the following.
U.S. Pat. No. 3,219,528, issued Nov. 23, 1965 to M. L. Thominet, discloses substituted benzamides of the formula ##STR4## in which R.sup.1 and R.sup.2 are alkyl, L is oxygen, methylene or NR in which R is hydrogen, alkyl or alkylsulfamoyl; W is alkylene; A is alkyl; B is sulfur or oxygen; and X, Y and Z are hydrogen, halogen, alkoxy, nitro, amino, alkylamino, dialkylamino, (lower)acyl, (lower)acylamino, cyano, alkylmercapto, sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl or halomethyl. The compounds are apomorphine antagonists and are stated to be antiemetic agents. U.S. Pat. Nos. 3,177,252, issued Apr. 6, 1965, and 3,312,739, issued Apr. 4, 1967, are related and have similar disclosures.
United Kingdom Patent No. 1,500,105, published Feb. 8, 1978, discloses substituted benzamides of the formula ##STR5## wherein A is hydrogen, C.sub.1-5 alkyl or C.sub.2-5 alkenyl; X is hydrogen, C.sub.1-5 alkoxy, C.sub.2-5 alkyl, C.sub.2-5 alkenyloxy or C.sub.2-5 alkenyl; Y is hydrogen, halogen, nitro, C.sub.1-5 alkyl, C.sub.1-5 alkoxy, amino or substituted amino; Z is hydrogen, halogen, C.sub.1-5 alkoxy, C.sub.1-5 alkylsulfonyl or a group of the formula --SO.sub.2 NR.sup.1 R.sup.2 in which R.sup.1 and R.sup.2 are the same or different and are hydrogen or a C.sub.1-5 alkyl group, or --NR.sup.1 R.sup.2 is a heterocyclic ring optionally containing another heteroatom; W is a C.sub.1-5 straight or branched chain alkylene group; B is --NR.sup.3 R.sup.4 in which R.sup.3 is C.sub.1-5 alkyl and R.sup.4 is C.sub.1-5 hydroxyalkyl, or B is a nitrogen-attached heterocyclic ring optionally containing a second nitrogen atom and optionally having a substituent, or B is a racemic, dextrorotatory or levorotatory heterocyclic ring of the formula ##STR6## in which R is C.sub.1-5 alkyl containing a reactive function such as hydroxy, mercapto, oxo, thioxo, oxa or thia; and m is 1, 2 or 3; and acid addition salts, oxides and quaternary ammonium salts thereof. The compounds are stated to be apomorphine antagonists and to have valuable therapeutic properties, particularly as antiemetics.
U.S. Pat. No. 4,207,327, issued June 10, 1980 to C. D. Lunsford et al., discloses compounds of the formula ##STR7## wherein R is alkyl, cycloalkyl or phenylalkyl; R.sup.1 is alkyl, cycloalkyl or phenylalkyl; R.sup.2 is hydrogen, alkyl or phenyl; and R.sup.3 is hydroxy, cyano, nitro, amino, fluoro, chloro, bromo, trifluoromethyl, alkyl, alkoxy, sulfamoyl or acetamido, and each R.sup.3 may be the same or different. The compounds are stated to have antiemetic and gastric emptying properties.
U.S. Pat. No. 3,966,957, issued June 29, 1976 to Cale, Jr., et al., discloses substituted benzamides of the formula ##STR8## wherein R is cycloalkyl, phenyl or phenylalkyl; R.sup.1 is hydrogen, C.sub.1-8 alkyl or phenyl; R.sup.2 is halogen, alkyl, alkoxy, amino, nitro, alkylamino, dialkylamino, mercaptomethyl, acetamido, sulfamoyl, cyano, hydroxy, benzyloxy or trifluoromethyl; and n is 0-3; and substituted thiobenzamides of the formula ##STR9## wherein R is cycloalkyl; R.sup.1 is hydrogen, or C.sub.1-8 alkyl; R.sup.2 is nitro, amino, halogen, sulfamoyl or alkoxy; and n is 0-3; and pharmaceutically acceptable acid addition salts thereof. U.S. Pat. No. 3,963,745 is related and has a substantially identical disclosure. The compounds are stated to be apomorphine antagonists and to be useful as antiemetics. Certain of the compounds were stated to reduce catalepsy in rats.